Retinal ganglion cell (RGC) survival is thought to depend on the level of activation of TrkB receptors by the endogenous neurotrophins, BDNF and NT4/5. These neurotrophins (NT) are derived from the superior colliculus, and complex with specific TrkB receptors. They then travel by retrograde axonal transport to the RCG cell body. There they act to preserve RGC by stimulating specific cell survival pathways, and by inhibiting specific cell death pathways (apoptosis). Elevated intraocular pressure (IOP), a major risk factor for glaucoma, obstructs axonal transport, and has been shown to inhibit delivery of NT to the RGC. In addition, there is good reason to believe that other risk factors for glaucoma, such as aging and previous optic nerve damage, may also affect this system, possibly by reducing the production of TrkB receptors, the production of NT, or both. These facts lead to the hypothesis that, in glaucoma, RGC death results from a reduction in the activation of neurotrophin-dependent TrkB mediated survival pathways. Using Brown Norway rats, methods now exist for modeling chronically elevated IOP, surgically lowering IOP, and studying these phenomena in aged, as well as young adult animals. This proposal will determine the effects of these three important glaucoma risk factors on neurotrophin TrkB activated survival signaling pathways and on RGC survival. A final specific aim will pharmacologically enhance the activity of NT-mediated cell survival pathways in partially damaged eyes following IOP control. This models the most common clinical situation in glaucoma. Success will be gauged by measuring decreased RGC loss, as well as changes in NT-mediated signaling pathways that enhance survival. These experiments will help to determine the potential for agents that enhance TrkB-activation in RGCs as a neuroprotective therapy for glaucoma.